A Study With NKT3447 for Adults With Advanced/Metastatic Solid Tumors

This is a Phase 1/1b, first-in-human, open-label, multicenter study of NKT3447 in adults with advanced/ metastatic solid tumors. The study consists of 2 parts, a Dose Escalation phase and a Dose Expansion phase. Eligible patients must have confirmed advanced/metastatic solid tumors (as outlined below) with disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available standard treatment likely to improve the disease outcome in the judgment of the investigator.

Dose Escalation:

1. Ovarian cancer
2. Endometrial cancer
3. Gastric cancer or gastroesophageal junction cancer
4. Small cell lung cancer
5. Triple-negative breast cancer (human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor negative)
6. Estrogen receptor/progesterone-receptor positive (ER+/PR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (must have progressed following treatment with a CDK4/6 inhibitor, and not suitable for endocrine therapy)
7. Other solid tumors with CCNE1 amplification as determined by next generation sequencing by local liquid or tissue biopsy.

Dose Expansion:

a. Platinum resistant or refractory ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least 1 platinum containing therapy with cyclin E amplification as determined by fluorescence in situ hybridization, quantitative polymerase chain reaction, or next-generation sequencing by local liquid or tissue biopsy.

The Dose Escalation phase will evaluate the safety, tolerability, and pharmacokinetics (PK) to determine the maximum tolerated dose (MTD) and/or preliminary recommended dose for expansion (RDE) of NKT3447 in adults with advanced or metastatic solid tumors.

The Dose Expansion phase will evaluate the safety, tolerability, pharmacokinetics (PK), and the preliminary antitumor activity of NKT3447 in adult subjects with CCNE1 amplified ovarian cancer at the RDEs selected in Dose Escalation and to determine the preliminary recommended RP2D.

• NKT3447 (Drug): Oral CDK2 inhibitor

Primary outcomes

• Number of Participants with Dose Limiting Toxicity (DLT) events [28 days]: DLTs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5 .0.
• Objective Response Rate (ORR) [1 year]: ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as determined by the Investigator

Secondary outcomes

• Progression-free survival (PFS) [2 years]: PFS defined as the time from the date the participant started study drug to the date the participant experiences an event of disease progression or death.
• Duration of Response (DOR) [2 years]: Duration of overall response is defined as the time from the date of first documented CR or PR, assessed by investigator and based on RECIST v. 1.1, to the documented date of progressive disease (PD) or death, whichever occurred first.
• Disease control rate [1 year]: Disease control rate defined as CR + PR + stable disease \[SD\]
• Overall Survival (OS) [2 years]: OS defined as the time from the date the participant started study drug to death for any reason.
• Time to Response (TTR) [1 year]: TTR is defined as the time from first dose to the first documented CR or PR which is subsequently confirmed.
• Number of Participants with Adverse Events [2 years]: An adverse event (AE) is defined as any untoward medical occurrence in a patient and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related.
• Maximum observed plasma concentration (Cmax) of NKT3447 [1 month]: Maximum observed plasma concentration (Cmax) of NKT3447
• Time to maximum observed plasma concentration of NKT3447 (Tmax) [1 month]: Time to maximum observed plasma concentration of NKT3447 (Tmax)
• Observed trough concentration of NKT3447 (Ctrough) [88 weeks]: Observed trough concentration of NKT3447 (Ctrough)
• Area under the plasma concentration-time curve (AUC0-t) of NKT3447 [1 month]: Area under the plasma concentration-time curve (AUC0-t) of NKT3447
• Apparent clearance (CL/F) [1 month]: Apparent clearance (CL/F)
• Apparent volume of distribution (V/F) [1 month]: Apparent volume of distribution (V/F)
• Half-life (t1/2) [1 month]: Half-life (t1/2)
• Accumulation ratio (AR) [1 month]: Accumulation ratio (AR)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Must have confirmed unresectable advanced/metastatic solid tumors (as outlined below) with disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available standard treatment likely to improve the disease outcome in the judgment of the Investigator.

  * Measurable disease per the RECIST v1.1
  * An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  * Able to swallow oral medications.

Dose Escalation(Part 1):

1. Ovarian cancer
2. Endometrial cancer
3. Gastric cancer or gastroesophageal junction cancer
4. Small cell lung cancer (SCLC)
5. Triple-negative breast cancer (human epidermal growth factor receptor 2 \[HER2\], estrogen receptor \[ER\], progesterone receptor negative)
6. ER/progesterone-receptor positive, HER2 negative breast cancer (must have progressed following treatment with a CDK4/6 inhibitor, and not suitable for endocrine therapy)
7. Other solid tumors with CCNE1 amplification as determined by NGS by local liquid or tissue biopsy.

Dose Expansion (Part 2):

a. Platinum resistant or refractory ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least 1 platinum containing therapy with CCNE1 amplification as determined by NGS by local liquid or tissue biopsy.

* Measurable disease per the RECIST v1.1
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Able to swallow oral medications.

Exclusion Criteria:

* Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.
* History of another malignancy with exceptions
* Visceral crisis with life-threatening complications, lymphangitic spread, CNS metastasis and/or carcinomatous meningitis
* Failed to recover from effects of prior anticancer treatment therapy to baseline or Grade ≤ 1 severity (per CTCAE)
* Clinically active interstitial lung disease
* History of uveitis, retinopathy or other clinically significant retinal disease
* Has known human immunodeficiency virus (HIV), active hepatitis B or C infection
* Prior CDK2 inhibitor
* Major surgery within 2 months or minor surgery within 10 days before the first dose of NKT3447